tbuckley/cabot-search huggingface dataset:
Inherited polymorphisms in the Human Leukocyte Antigen Region modify the association between varicella-zoster virus antibody reactivity and glioma prognosis
Authors: Stephen S Francis, Geno Guerra, Helen M Hansen, George Wendt, Linda Kachuri, John K Wiencke, Margaret Wrensch
Journal: Neuro-Oncology (2023)

Journal Article Inherited polymorphisms in the Human Leukocyte Antigen Region modify the association between varicella-zoster virus antibody reactivity and glioma prognosis Get access Stephen S Francis, Stephen S Francis Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USADepartment of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USAWeill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA Corresponding Author: Stephen S. Francis, MS, PhD, Department of Neurological Surgery, Weill Institute for Neurosciences, University of California San Francisco, 1450 3rd St, San Francisco, CA 94158USA (Stephen.Francis@ucsf.edu). https://orcid.org/0000-0002-6488-6272 Search for other works by this author on: Oxford Academic PubMed Google Scholar Geno Guerra, Geno Guerra Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USADepartment of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA https://orcid.org/0000-0001-9870-9998 Search for other works by this author on: Oxford Academic PubMed Google Scholar Helen M Hansen, Helen M Hansen Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar George Wendt, George Wendt Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Linda Kachuri, Linda Kachuri Department of Epidemiology and Population Health, Stanford University, Stanford, California, USAStanford Cancer Institute, Stanford University, Stanford, California, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar John K Wiencke, John K Wiencke Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USAWeill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Margaret Wrensch Margaret Wrensch Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 10, October 2023, Pages 1910–1912, https://doi.org/10.1093/neuonc/noad122 Published: 18 August 2023 Article history Corrected and typeset: 18 August 2023 Published: 18 August 2023
CAR-T in the Treatment of Acute Myeloid Leukemia: Barriers and How to Overcome Them
Authors: Jolien Vanhooren, Rani Dobbelaere, Charlotte Derpoorter, Larissa Deneweth, Laurens Van Camp, Anne Uyttebroeck, Barbara De Moerloose, Tim Lammens
Journal: HemaSphere (2023)

Conventional therapies for acute myeloid leukemia (AML) are characterized by high rates of relapse, severe toxicities, and poor overall survival rates. Thus, the development of new therapeutic strategies is crucial for improving the survival and quality of life of AML patients. CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapy has been extremely successful in the treatment of B-cell acute lymphoid leukemia and several mature B-cell lymphomas. However, the use of CAR T-cell therapy for AML is currently prevented due to the lack of a myeloid equivalent to CD19, as currently known cell surface targets on leukemic blasts are also expressed on healthy hematopoietic stem and progenitor cells as well as their progeny. In addition, the immunosuppressive tumor microenvironment has a dampening effect on the antitumor activity of CAR-T cells. Here, we review the therapeutic challenges limiting the use of CAR T-cell therapy for AML and discuss promising novel strategies to overcome them.
Genome-wide transcription factor–binding maps reveal cell-specific changes in the regulatory architecture of human HSPCs
Authors: Shruthi Subramanian, Julie A. I. Thoms, Yizhou Huang, Paola Cornejo-Páramo, Forrest C. Koch, Sebastien Jacquelin, Sylvie Shen, Emma Song, Swapna Joshi, Chris Brownlee, Petter S. Woll, Diego Chacon-Fajardo, Dominik Beck, David J. Curtis, Kenneth Yehson, Vicki Antonenas, Tracey O'Brien, Annette Trickett, Jason A. Powell, Ian D. Lewis, Stuart M. Pitson, Maher K. Gandhi, Steven W. Lane, Fatemeh Vafaee, Emily S. Wong, Berthold Göttgens, Hamid Alinejad-Rokny, Jason W. H. Wong, John E. Pimanda
Journal: Blood (2023)
PPM1D modulates hematopoietic cell fitness and response to DNA damage and is a therapeutic target in myeloid malignancy
Authors: Peter G. Miller, Adam S. Sperling, Christina Mayerhofer, Marie E. McConkey, Jana M. Ellegast, Carmen Da Silva, Drew N. Cohen, Chuqi Wang, Azeem Sharda, Ni Yan, Subha Saha, Cameron Schluter, Ilexa Schechter, Mikołaj Słabicki, Brittany Sandoval, Josephine Kahn, Steffen Boettcher, Christopher J. Gibson, David T. Scadden, Kimberly Stegmaier, Shruti Bhatt, R. Coleman Lindsley, Benjamin L. Ebert
Journal: Blood (2023)

Abstract PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of PPM1D in hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover a central role for Ppm1d in hematopoiesis and validate its potential as a therapeutic target. We find that Ppm1d regulates the competitive fitness and self-renewal of hematopoietic stem cells (HSCs) with and without exogenous genotoxic stresses. We also show that although Ppm1d activation confers cellular resistance to cytotoxic therapy, it does so to a lesser degree than p53 loss, informing the clonal competition phenotypes often observed in human studies. Notably, loss of Ppm1d sensitizes leukemias to cytotoxic therapies in vitro and in vivo, even in the absence of a Ppm1d mutation. Vulnerability to PPM1D inhibition is observed across many cancer types and dependent on p53 activity. Importantly, organism-wide loss of Ppm1d in adult mice is well tolerated, supporting the tolerability of pharmacologically targeting PPM1D. Our data link PPM1D gain-of-function mutations to the clonal expansion of HSCs, inform human genetic observations, and support the therapeutic targeting of PPM1D in cancer.
Fractionated vs single-dose gemtuzumab ozogamicin with determinants of benefit in older patients with AML: the UK NCRI AML18 trial
Authors: Sylvie D. Freeman, Abin Thomas, Ian Thomas, Robert K. Hills, Paresh Vyas, Amanda Gilkes, Marlen Metzner, Niels Asger Jakobsen, Alison Kennedy, Rachel Moore, Nuria Marquez Almuina, Sarah Burns, Sophie King, Georgia Andrew, Kathleen M. E. Gallagher, Rob S. Sellar, Paul Cahalin, Duruta Weber, Mike Dennis, Priyanka Mehta, Steven Knapper, Nigel H. Russell
Journal: Blood (2023)

Abstract Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomized 852 older adults (median age, 68-years) with AML/high-risk myelodysplasia to GO on day 1 (GO1) or on days 1 and 4 (GO2) of course 1 induction. The median follow-up period was 50.2 months. Although complete remission (CR) rates after course 1 did not significantly differ between arms (GO2, 63%; GO1, 57%; odds ratio [OR], 0.78; P = .08), there were significantly more patients who achieved CR with a measurable residual disease (MRD)&amp;lt;0.1% (50% vs 41%; OR, 0.72; P = .027). This differential MRD reduction with GO2 varied across molecular subtypes, being greatest for IDH mutations. The 5-year overall survival (OS) was 29% for patients in the GO2 arm and 24% for those in the GO1 arm (hazard ratio [HR], 0.89; P = .14). In a sensitivity analysis excluding patients found to have adverse cytogenetics or TP53 mutations, the 5-year OS was 33% for GO2 and 26% for GO1 (HR, 0.83; P = .045). In total, 228 (27%) patients received an allogeneic transplantation in first remission. Posttransplant OS was superior in the GO2 arm (HR, 0.67; P = .033); furthermore, the survival advantage from GO2 in the sensitivity analysis was lost when data of patients were censored at transplantation. In conclusion, GO2 was associated with a greater reduction in MRD and improved survival in older adults with nonadverse risk genetics. This benefit from GO2 was dependent on allogeneic transplantation to translate the better leukemia clearance into improved survival. This trial was registered at www.isrctn.com as #ISRCTN 31682779.
Targeting endothelial vascular cell adhesion molecule-1 in atherosclerosis: drug discovery and development of vascular cell adhesion molecule-1–directed novel therapeutics
Authors: Jessica R Pickett, Yuao Wu, Lucia F Zacchi, Hang T Ta
Journal: Cardiovascular Research (2023)

Abstract Vascular cell adhesion molecule-1 (VCAM-1) has been well established as a critical contributor to atherosclerosis and consequently as an attractive therapeutic target for anti-atherosclerotic drug candidates. Many publications have demonstrated that disrupting the VCAM-1 function blocks monocyte infiltration into the sub-endothelial space, which effectively prevents macrophage maturation and foam cell transformation necessary for atherosclerotic lesion formation. Currently, most VCAM-1-inhibiting drug candidates in pre-clinical and clinical testing do not directly target VCAM-1 itself but rather down-regulate its expression by inhibiting upstream cytokines and transcriptional regulators. However, the pleiotropic nature of these regulators within innate immunity means that optimizing dosage to a level that suppresses pathological activity while preserving normal physiological function is extremely challenging and oftentimes infeasible. In recent years, highly specific pharmacological strategies that selectively inhibit VCAM-1 function have emerged, particularly peptide- and antibody-based novel therapeutics. Studies in such VCAM-1–directed therapies so far remain scarce and are limited by the constraints of current experimental atherosclerosis models in accurately representing the complex pathophysiology of the disease. This has prompted the need for a comprehensive review that recounts the evolution of VCAM-1–directed pharmaceuticals and addresses the current challenges in novel anti-atherosclerotic drug development.
Targeting cancer hallmark vulnerabilities in hematologic malignancies by interfering with Hedgehog/GLI signaling
Authors: Peter W. Krenn, Fritz Aberger
Journal: Blood (2023)

Abstract Understanding the genetic alterations, disrupted signaling pathways, and hijacked mechanisms in oncogene-transformed hematologic cells is critical for the development of effective and durable treatment strategies against liquid tumors. In this review, we focus on the specific involvement of the Hedgehog (HH)/GLI pathway in the manifestation and initiation of various cancer features in hematologic malignancies, including multiple myeloma, T- and B-cell lymphomas, and lymphoid and myeloid leukemias. By reviewing canonical and noncanonical, Smoothened-independent HH/GLI signaling and summarizing preclinical in vitro and in vivo studies in hematologic malignancies, we elucidate common molecular mechanisms by which HH/GLI signaling controls key oncogenic processes and cancer hallmarks such as cell proliferation, cancer stem cell fate, genomic instability, microenvironment remodeling, and cell survival. We also summarize current clinical trials with HH inhibitors and discuss successes and challenges, as well as opportunities for future combined therapeutic approaches. By providing a bird's eye view of the role of HH/GLI signaling in liquid tumors, we suggest that a comprehensive understanding of the general oncogenic effects of HH/GLI signaling on the formation of cancer hallmarks is essential to identify critical vulnerabilities within tumor cells and their supporting remodeled microenvironment, paving the way for the development of novel and efficient personalized combination therapies for hematologic malignancies.
Malignancy-associated hemophagocytic lymphohistiocytosis in Sweden: incidence, clinical characteristics, and survival
Authors: Alexandra Löfstedt, Martin Jädersten, Marie Meeths, Jan-Inge Henter
Journal: Blood (2023)

Abstract We evaluated malignancy-associated hemophagocytic lymphohistiocytosis (mal-HLH) in Sweden regarding population-based incidence, clinical features, and survival. From 1997 to 2018, we identified 307 adults (≥18 years old) and 9 children (209 males, 107 females; P &amp;lt; .001) with both an HLH-related diagnosis and malignant disease, corresponding to 0.19 per 100 000 adults annually (0.15/100 000 for the entire population), increasing from 0.026 (1997-2007) to 0.34 (2008-2018) (P &amp;lt; .001). In the latest 7-year period (2012-2018), the annual incidence was 0.45 per 100 000 adults (n = 246). This incidence varied between the 6 health care regions in Sweden, from 0.18 to 0.71 (Region Stockholm) per 100 000 adults annually (P &amp;lt; .001), likely due to variable awareness. Mal-HLH was reported in 0.6% of all hematological malignancies, with the highest proportion (2.5%) in young males. Among the 316 patients, the 1-month probability of survival, likely representing the HLH episode, increased significantly from 52% (95% confidence interval [CI], 40-63) (1997-2007) to 71% (95% CI, 65-76) (2008-2018), whereas 2-year survival remained poor (25%; 95% CI, 20-30). Altogether, 52% were lymphomas, 29% leukemias, 8% other hematological malignancies, and 11% solid tumors. Males were more affected than females by mal-HLH, also taking the over-representation of males with hematological malignancies into account (P = .0012). Validation by medical-file reviews revealed 13% over-reporting of HLH. We conclude that the annual mal-HLH incidence has increased 10-fold and was at least 0.71 per 100 000 adults from 2012 to 2018, that is, 0.62 per 100 000 adults considering 13% estimated HLH over-reporting, and that early survival improved significantly, likely due to increased awareness and more HLH-directed therapy.
Neurotransmitters in the Mammalian Circadian System
Authors: B Rusak, K G Bina
Journal: Annual Review of Neuroscience (1990)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Discrimination, feeling undervalued, and health-care workforce attrition: an analysis from the UK-REACH study
Authors: Christopher A Martin, Asta Medisauskaite, Mayuri Gogoi, Lucy Teece, Joshua Nazareth, Daniel Pan, Sue Carr, Kamlesh Khunti, Laura B Nellums, Katherine Woolf, Manish Pareek
Journal: The Lancet (2023)
Measuring chronic myeloid leukaemia TKI-related toxic effects in the real world: a systematic review and critical assessment of content validity of patient-reported outcome measures
Authors: Yolba Smit, Sanne J J P M Metsemakers, Jeroen J W M Janssen, Eduardus F M Posthuma, Iris Walraven, Rosella P M G Hermens, Nicole M A Blijlevens
Journal: The Lancet Haematology (2023)
Author correction to ‘Real-time SERS monitoring anticancer drug release along with SERS/MR imaging for pH-sensitive chemo-phototherapy’ [Acta Pharm Sin B 13 (2023) 1303–1317]
Authors: Xueqin Huang, Bingbing Sheng, Hemi Tian, Qiuxia Chen, Yingqi Yang, Brian Bui, Jiang Pi, Huaihong Cai, Shanze Chen, Jianglin Zhang, Wei Chen, Haibo Zhou, Pinghua Sun
Journal: Acta Pharmaceutica Sinica B (2023)

[This corrects the article DOI: 10.1016/j.apsb.2022.08.024.].
Revisiting the minimum incubation period of Zaire ebolavirus
Authors: Aaron D Kofman, Dana L Haberling, Gisele Mbuyi, Lise D Martel, Amy N Whitesell, Michel Van Herp, Gerry Makaya, Salomon Corvil, Aaron Aruna Abedi, Patrick Mavungu Ngoma, Francis Mbuyi, Mathias Mossoko, Enogo Koivogui, Norbert Soke, Nouonan Gbamou, Peter N Fonjungo, Lamine Keita, Sakoba Keita, Trevor R Shoemaker, Guy A Richards, Joel M Montgomery, Joel G Breman, Thomas W Geisbert, Mary J Choi, Pierre E Rollin
Journal: The Lancet Infectious Diseases (2023)
Bintrafusp Alfa Versus Pembrolizumab in Patients With Treatment-Naive, Programmed Death-Ligand 1–High Advanced NSCLC: A Randomized, Open-Label, Phase 3 Trial
Authors: Byoung Chul Cho, Jong Seok Lee, Yi-Long Wu, Irfan Cicin, Manuel Cobo Dols, Myung-Ju Ahn, Kristof Cuppens, Rémi Veillon, Ernest Nadal, Josiane Mourão Dias, Claudio Martin, Martin Reck, Edward B. Garon, Enriqueta Felip, Luis Paz-Ares, Francoise Mornex, Everett E. Vokes, Alex A. Adjei, Clifford Robinson, Masashi Sato, Yulia Vugmeyster, Andreas Machl, Francois Audhuy, Surendra Chaudhary, Fabrice Barlesi
Journal: Journal of Thoracic Oncology (2023)
Hippo pathway-manipulating neutrophil-mimic hybrid nanoparticles for cardiac ischemic injury via modulation of local immunity and cardiac regeneration
Authors: Qiaozi Wang, Yanan Song, Jinfeng Gao, Qiyu Li, Jing Chen, Yifang Xie, Zhengmin Wang, Haipeng Tan, Hongbo Yang, Ning Zhang, Juying Qian, Zhiqing Pang, Zheyong Huang, Junbo Ge
Journal: Acta Pharmaceutica Sinica B (2023)

The promise of regeneration therapy for restoration of damaged myocardium after cardiac ischemic injury relies on targeted delivery of proliferative molecules into cardiomyocytes whose healing benefits are still limited owing to severe immune microenvironment due to local high concentration of proinflammatory cytokines. Optimal therapeutic strategies are therefore in urgent need to both modulate local immunity and deliver proliferative molecules. Here, we addressed this unmet need by developing neutrophil-mimic nanoparticles NM@miR, fabricated by coating hybrid neutrophil membranes with artificial lipids onto mesoporous silica nanoparticles (MSNs) loaded with microRNA-10b. The hybrid membrane could endow nanoparticles with strong capacity to migrate into inflammatory sites and neutralize proinflammatory cytokines and increase the delivery efficiency of microRNA-10b into adult mammalian cardiomyocytes (CMs) by fusing with cell membranes and leading to the release of MSNs-miR into cytosol. Upon NM@miR administration, this nanoparticle could home to the injured myocardium, restore the local immunity, and efficiently deliver microRNA-10b to cardiomyocytes, which could reduce the activation of Hippo-YAP pathway mediated by excessive cytokines and exert the best proliferative effect of miR-10b. This combination therapy could finally improve cardiac function and mitigate ventricular remodeling. Consequently, this work offers a combination strategy of immunity modulation and proliferative molecule delivery to boost cardiac regeneration after injury.
Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease
Authors: Laura R. Claus, Chuan Chen, Jennifer Stallworth, Joshua L. Turner, Gisela G. Slaats, Alexandra L. Hawks, Holly Mabillard, Sarah R. Senum, Sujata Srikanth, Heather Flanagan-Steet, Raymond J. Louie, Josh Silver, Jordan Lerner-Ellis, Chantal Morel, Chloe Mighton, Frank Sleutels, Marjon van Slegtenhorst, Tjakko van Ham, Alice S. Brooks, Eiske M. Dorresteijn, Tahsin Stefan Barakat, Karin Dahan, Nathalie Demoulin, Eric Jean Goffin, Eric Olinger, John C. Ambrose, Prabhu Arumugam, Roel Bevers, Marta Bleda, Freya Boardman-Pretty, Christopher R. Boustred, Helen Brittain, Mark J. Caulfield, Georgia C. Chan, Greg Elgar, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Athanasios Kousathanas, Lea Lahnstein, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Meriel McEntagart, Federico Minneci, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Chris A. Odhams, Christine Patch, Mariana Buongermino Pereira, Daniel Perez-Gil, John Pullinger, Tahrima Rahim, Augusto Rendon, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, Mélanie Tanguy, Ana Lisa Taylor Tavares, Ellen R.A. Thomas, Simon R. Thompson, Arianna Tucci, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Martin Larsen, Jens Michael Hertz, Marc R. Lilien, Lena Obeidová, Tomas Seeman, Hillarey K. Stone, Larissa Kerecuk, Mihai Gurgu, Fjodor A. Yousef Yengej, Carola M.E. Ammerlaan, Maarten B. Rookmaaker, Christian Hanna, R. Curtis Rogers, Karen Duran, Edith Peters, John A. Sayer, Gijs van Haaften, Peter C. Harris, Kun Ling, Jennifer M. Mason, Albertien M. van Eerde, Richard Steet
Journal: Kidney International (2023)
Cancer cell membrane-coated bacterial ghosts for highly efficient paclitaxel delivery against metastatic lung cancer
Authors: Dandan Ling, Xueli Jia, Ke Wang, Qiucheng Yan, Bochuan Yuan, Lina Du, Miao Li, Yiguang Jin
Journal: Acta Pharmaceutica Sinica B (2023)

Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer, although it is limited by the low tumor delivery efficacy of anticancer drugs. Bacterial therapy is emerging for cancer treatment due to its high immune stimulation effect; however, excessively generated immunogenicity will cause serious inflammatory response syndrome. Here, we prepared cancer cell membrane-coated liposomal paclitaxel-loaded bacterial ghosts (LP@BG@CCM) by layer-by-layer encapsulation for the treatment of metastatic lung cancer. The preparation processes were simple, only involving film formation, electroporation, and pore extrusion. LP@BG@CCM owned much higher 4T1 cancer cell toxicity than LP@BG due to its faster fusion with cancer cells. In the 4T1 breast cancer metastatic lung cancer mouse models, the remarkably higher lung targeting of intravenously injected LP@BG@CCM was observed with the almost normalized lung appearance, the reduced lung weight, the clear lung tissue structure, and the enhanced cancer cell apoptosis compared to its precursors. Moreover, several major immune factors were improved after administration of LP@BG@CCM, including the CD4+/CD8a+ T cells in the spleen and the TNF-α, IFN-γ, and IL-4 in the lung. LP@BG@CCM exhibits the optimal synergistic chemo-immunotherapy, which is a promising medication for the treatment of metastatic lung cancer.